Our brain must alter the way in which it processes sensory information based on the present physiological needs of the individual. For instance, our olfactory and gustatory systems are much more acute when we are hungry. To achieve this flexibility the nervous system relies on the release of neuromodulators which alter the response properties of neurons to optimize the ability of the nervous system to process information in the appropriate context. Neuromodulation is a ubiquitous feature of the nervous system and thus many neurological disorders, such as schizophrenia and depression, arise from dysfunctional neuromodulatory systems. Despite the importance of neuromodulation for healthy sensory processing, our ability to predict the consequences of neuromodulation has been limited due to the diversity of neuromodulatory receptor types expressed in the vertebrate nervous system (for instance, vertebrates possess 14 serotonin receptors). In this application, we propose to address this knowledge deficit by using a model sensory system with fewer receptors (5 serotonin receptors as opposed to 14), the olfactory system of Drosophila. The objective of this application is to determine the functional patterns of serotonin receptor expression within the olfactory system of Drosophila and the contribution of individual receptors towards the modulation of sensory input by serotonin. The long-term goal of this research is to determine how individual receptors expressed by distinct functional classes of neurons each contribute to the network level effects of neuromodulation. In the vertebrate and invertebrate olfactory system, serotonin enhances the odor-evoked responses within the physiological context of the waking state. However, without knowing the functional identity of neurons expressing each serotonin receptor, it is very difficult to determine which features of olfactory processing are directly altered resulting in the network-wide effects of serotonin. In Specific Aim 1 we will use immunocytochemistry in combination with genetic tagging to determine the transmitter content of the neurons expressing each of the four serotonin receptor types. To understand the contribution of any given receptor to the network-level effects of a neuromodulator, it is critical to understand the consequences of receptor activation for each functional neuronal type expressing a given receptor. In Specific Aim 2 we will manipulate the expression levels of a single serotonin receptor in a functionally discrete set of sensory neurons and use behavioral assays to determine the extent to which modulation of sensory neuron input by a single serotonin receptor influences olfactory processing.